System for noninvasive hematocrit monitoring

ABSTRACT

A system determines heamtocrit transcutaneously and noninvasively. Disclosed are a finger clip assembly and an earlobe clip assembly, each including at least a pair of emitters and a photodiode in appropriate alignment to enable operation in either a transmissive mode or a reflectance mode. At least two, and preferably three, predetermined wavelengths of light are assed onto or through body tissues such as the finger, earlobe, or scalp, etc. and the extinction of each wavelength is detected. Mathematical manipulation of the detected values compensates for the effects of body tissue and fluid and determines the hematocrit value. If a fourth wavelength of light is used which is extinguished substantially differently by oxyhemoglobin and reduced hemoglobin and which is not substantially extinguished by plasmas, then the blood oxygen saturation value, independent of hematocrit, maybe determined. It is also disclosed how to detect and analyze multiple wavelengths using a logarithmic DC analysis technique. Then a pulse wave is not required. So this method may be utilized in states of low blood pressure or low blood flow.

This is a continuation of U.S. application Ser. No. 09/084,958, filedMay 28, 1998, now U.S. Pat. No. 6,266,546, which is a continuation ofU.S. application Ser. No. 08/479,352, filed Jun. 7, 1995, now U.S. Pat.No. 5,803,908, which is a continuation of U.S. application Ser. No.08/317,726, filed Oct. 4, 1994, now U.S. Pat. No. 5,499,627, which is adivisional of U.S. application Ser. No. 08/011,882, filed Feb. 1, 1993,now U.S. Pat. No. 5,372,136, which is a continuation of U.S. applicationSer. No. 07/598,169, filed Oct. 16, 1990 (abandoned).

BACKGROUND

1. The Field of the Invention

This invention relates to systems and methods for noninvasivelymeasuring one or more biologic constituent values. More particularly,the present invention relates to noninvasive spectrophotometric systemsand methods for quantitatively and continuously monitoring thehematocrit and other blood parameters of a subject.

2. The Prior Art

Modern medical practice utilizes a number of procedures and indicatorsto assess a patient's condition. One of these indicators is thepatient's hematocrit. Hematocrit (often abbreviated as Hct) is thevolume, expressed as a percentage, of the patient's blood which isoccupied by red corpuscles (commonly referred to as red blood cells).

Human blood consists principally of liquid plasma (which is comprised ofover 90% water with more than 100 other constituents such as proteins,lipids, salts, etc.) and three different corpuscles. The threecorpuscles found in blood are red corpuscles, white corpuscles, andplatelets.

The chief function of red corpuscles is to carry oxygen from the lungsto the body tissues and carbon dioxide from the tissues to the lungs.This critical life supporting function is made possible by hemoglobinwhich is the principal active constituent of red corpuscles. In thelungs, hemoglobin rapidly absorbs oxygen to form oxyhemoglobin whichgives it a bright scarlet color. As the red corpuscles travel to thetissues, the oxyhemoglobin releases oxygen, i.e., is reduced, and thehemoglobin turns a dark red color.

The oxygen transportation functions of the body rely essentiallyentirely on the presence of hemoglobin in the red corpuscles. Redcorpuscles greatly outnumber other corpuscles being about 700 timesgreater than the number of white corpuscles in a healthy human subject;

Medical professionals routinely desire to know the hematocrit of apatient. In order to determine hematocrit using any of the techniquesavailable to date, it is necessary to draw a sample of blood bypuncturing a vein or invading a capillary. Then, using a widely acceptedtechnique, the sample of blood is subjected to a high speed centrifugetreatment for several minutes (e.g., 7 or more minutes). Thecentrifuging process, if properly carried out, separates the corpusclesinto a packed mass. The volume occupied by the packed corpuscles,expressed as a percentage of the total volume of the plasma/corpusclecombination, is taken as the hematocrit.

It will be appreciated that the centrifuge process provides a hematocritvalue which includes all corpuscles, not just red corpuscles.Nevertheless, the vastly greater numbers of red corpuscles in a healthysubject allows the hematocrit value obtained by the centrifuge processto be clinically, usable in such healthy subjects. Nevertheless, insubjects with low hematocrit or dramatically high white corpusclecontent, it may be desirable to diminish the effect of the non-redcorpuscles when obtaining an hematocrit value.

There have been various techniques and devices introduced which haveautomated and increased the precision of obtaining a hematocrit value.Nevertheless, all the previously available techniques have one or moredrawbacks.

Specifically, the previously available techniques all require that asample of blood be withdrawn from the patient for in vitro analysis. Anyinvasion of the subject to obtain blood is accompanied by the problemsof inconvenience, stress, and discomfort imposed upon the subject andalso the risks which are always present when the body is invaded.Drawing blood also creates certain contamination risks to theparamedical professional. Moreover, even in a setting where obtaining ablood sample does not impose any additional problems, e.g., duringsurgery, the previously available techniques require a delay between thetime that the sample is drawn and the hematocrit value is obtained.Still further, none of the previously available techniques allowcontinuous monitoring of a subject's hematocrit, as might be desirableduring some surgical procedures or intensive care treatment, but requirethe periodic withdrawal and processing of blood samples.

In view of the drawbacks inherent in the available art dealing withinvasive hematocrit determinations, it would be an advance in the art tononinvasively and quantitatively determine a subject's hematocrit value.It would also be an advance in the art to provide a system and methodfor noninvasive hematocrit monitoring which can be applied to aplurality of body parts and which utilizes electromagnetic emissions asan hematocrit information carrier. It would be another advance in theart to provide a system and method which can provide both immediate andcontinuous hematocrit information for a subject. It would be yet anotheradvance to provide repeatable and reliable systems for noninvasivemonitoring of a subject's hematocrit. It would be still another advancein the art to noninvasively and accurately determine a subject's bloodoxygen saturation while accounting for the patient's low or varyinghematocrit and/or under conditions of low perfusion.

BRIEF SUMMARY AND OBJECTS OF THE INVENTION

The present invention is directed to apparatus and methods fordetermining biologic constituent values, such as the hematocrit value,transcutaneously and noninvasively. This is achieved by passing at leasttwo wavelengths of light onto or through body tissues such as thefinger, earlobe, or scalp, etc. and then compensating for the effectsbody tissue and fluid effects. As used herein, the term biologicconstituent includes proteins, red cells, metabolites, drugs,cytochromes, hormones, etc.

In one embodiment within the scope of the present invention, thewavelengths of light are selected to be near or at the isobestic pointsof reduced hemoglobin and oxyhemoglobin to eliminate the effects ofvariable blood oxygenation. At an isobestic wavelength, the extinctioncoefficient, ε, is the same for both reduced and oxygenated hemoglobin.Thus, at isobestic wavelengths, the amount of light absorption isindependent of the amount of oxygenated or reduced hemoglobin in the redcells.

Means are provided for delivering and detecting those wavelengths oflight and for analyzing the light intensities. The sensing and radiationemitting elements are preferably spatially arranged to allow ease of useand to be accessible to a patient's exterior body parts. Theconfiguration of the sensing and emitting elements is important to giveoptimum repeatability of the signals and data derived therefrom.

Memory and calculation means are included which are capable of storing,manipulating, and displaying the detected signals in a variety of ways.For instance, the continuous pulse wave contour, the pulse rate value,the hematocrit value and the continuous analog hematocrit curve in realtime, the hematocrit-independent oxygen saturation value, and the oxygencontent value of the blood, all as digital values or as continuousanalog curves in real time are capable of being displayed.

An important advantage of monitoring and analyzing each individualpulsatile signal is that averaging algorithms may be performed foridentifying and rejecting erroneous data. In addition, such techniquesalso improve repeatability.

Another significant advantage of the present invention is the capabilityof monitoring multiple wavelengths (including nonisobestic wavelengths)for the simultaneous real time computation and display of thehematocrit-independent oxygen saturation value. Techniques in prior artoximetry have all suffered inaccuracies due to hematocrit sensitivities.

Rather than apply AC-DC cancellation techniques only, it is also withinthe scope of the present invention to detect and analyze multiplewavelengths using a logarithmic DC analysis technique. In thisembodiment, a pulse wave is not required. Hence, this embodiment may beutilized in states of low blood pressure or low blood flow.

It is, therefore, a primary object of the present invention to provide asystem and method for noninvasively and quantitatively determining asubject's hematocrit or other blood constituent value.

It is another object of the present invention to noninvasively determinethe hematocrit of a subject by utilizing electromagnetic radiation asthe transcutaneous information carrier.

It is another object of the present invention to provide a noninvasivehematocrit monitor which may be used on various body parts and whichprovides accurate quantitative hematocrit values.

It is another object of the present invention to provide a system andmethod which can provide immediate and continuous hematocrit informationfor a subject.

It is yet another object of the present invention to provide arepeatable and reliable system for noninvasive monitoring of a subject'shematocrit.

It is still another object of the present invention to provide a systemand method for noninvasively determining a subjects's blood oxygensaturation (S_(a)O₂) independent of the subject's hematocrit.

It is still another object of the present invention to provide a systemand method for noninvasively determining a subject's hematocrit and/orblood oxygen saturation even under conditions of low perfusion (lowblood flow).

These and other objects and advantages of the invention will become morefully apparent from the description and claims which follows, or may belearned by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective, view of a first presently preferred embodimentof the present invention.

FIG. 1A is an enlarged cross sectional view of the body part (finger)and system components represented in FIG. 1 used in a transmission mode.

FIG. 1B is an enlarged cross sectional view of the body part (finger)and associated system components represented in FIG. 1 used in areflective mode.

FIG. 2 is a chart showing the optical absorption coefficients ofoxyhemoglobin (HbO₂), reduced hemoglobin (Hb), and water (H₂O) versuswavelength.

FIG. 3 is a chart showing the relationship between the ratio of theextinction coefficients of two rays having differing wavelengths versushematocrit.

FIGS. 4A-4D provide a flow chart showing the steps carried out duringone presently preferred method of the present invention using apulsatile component of the subject's blood flow to provide accuratehematocrit and blood oxygen saturation values.

FIG. 5 is a perspective view of a second presently preferred system ofthe present invention which is applied to the ear and includesstructures to squeeze out the blood to blanch the ear tissues.

FIG. 5A is an enlarged cross sectional view of the ear and systemcomponents

FIG. 6 provides a detailed schematic diagram of the low level sensorcircuitry included in the presently preferred system of the presentinvention.

FIGS. 7A-7C provide a detailed schematic diagram digital sectioncircuitry included in the presently preferred system of the presentinvention.

FIGS. 8A-8D provide a detailed schematic diagram of the analog sectioncircuitry included in the presently preferred system of the presentinvention.

FIGS. 9A-9C provide a detailed schematic diagram of the power supply andinput/output (I/O) section included in the presently preferred system ofthe present invention.

FIG. 10 is a graph showing variation in oxygen saturation as a functionof hematocrit.

FIG. 11 is a graph of ε_(b805)/ε_(b970) versus Hematocrit.

FIGS. 12A-12B are graphs of ε versus Hematocrit at two non-preferredwavelengths and ε₁/ε₂ versus Hematocrit at those non-preferredwavelengths.

FIGS. 13A-13B are graphs of ε versus Heniatocrit at two non-preferredwavelengths and ε₁/ε₂ versus Hematocrit at those non-preferredwavelengths.

FIG. 14 illustrates vertical sensor-emitter alignment and the resultingnon-identical ΔX_(b) regions.

FIG. 15 illustrates horizontal sensor emitter alignment.

FIG. 16 is a chart showing the relationship between the extinctioncoefficient of light at three different wavelengths versus hematocritfor whole blood.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to apparatus and methods fordetermining biologic constituent values, such as the hematocrit value,transcutaneously and noninvasively. This is achieved by passing at leasttwo wavelengths of light onto or through body tissues such as thefinger, earlobe, or scalp, etc., and then compensating for the effectsof body tissue and fluid by modifying the Beer-Lambert Law. Theprinciples within the scope of the present invention may also beutilized to provide a hematocrit-independent oxygen saturation andoxygen content measurements as well as noninvasive measurement of bloodconstituents such as glucose, cholesterol, bilirubin, creatinine, etc.

Although the present invention will describe in great detail thetransillumination of various body parts, it will be appreciated thatreflectance spectrophotometry may alternatively be employed wheretransillumination is difficult to accomplish. As used herein, the term“body part” is intended to include skin, earlobe, finger, lip, forehead,etc. Because the principles within the scope of the present inventioncan be adapted by those skilled in the art for in vitro measurement ofhematocrit and other blood constituents, the discussion relating to bodyparts is intended to apply to various in vitro blood containers such astubes and cuvettes.

1. Spectrophotometric Methods

Spectrophotometric methods have been described in the prior art whichmonitor various metabolites in body fluids. Radiation, typically in thevisible or near infrared region, is directed onto an exterior body partfor transcutaneous penetration of the radiation. The radiation is thenmonitored reflectively or transmissively by a photodetector or similarsensor. Radiation spectra are chosen at wavelengths where the metaboliteor compound sought for either absorbs highly or poorly. Some examples ofsuch spectrophotometric methods are described in U.S. Pat. No. 4,653,498for pulse oximetry, U.S. Pat. No. 4,655,225 for blood glucosemonitoring, and more recently U.S. Pat. No. 4,805,623 for monitoringvarious blood metabolites (glucose, cholesterol, etc.).

A theoretical basis for the spectrophotometric techniques is theBeer-Lambert Law:

I=I ₀ e ^(−εXd)  (1)

Equation (1) may also be written:

ln (I/I ₀)=−εXd  (1a)

wherein I₀ is the incident intensity of the source radiation, I is thetransmitted intensity of the source through the sample, ε is theextinction coefficient of the sought for component, X is theconcentration of the sample component in the tissue itself, and d is theoptical path length (distance).

The Beer-Lambert Law (1) permits in vitro solute concentrationdeterminations. However, quantitative measurements have not beenpossible in the body since the scattering of the incident photonspassing into and through the integument and subdermal regions isextensive and highly variable. This scattering spoils the Beer-LambertLaw by adding a variable loss of radiation to the measurement and alsoextends the path length of the incident photons by an unknown amount aswell.

Even though optical pulse rate monitors, plethysmographs, and pulseoximeters are known, their development has been accelerated bytechniques which allow for cancellation of the optical scatteringeffects to a large extent. This development began with U.S. Pat. No.2,706,927 and was further refined by Yoshiya, et. al. (Med. and Biol.Eng. and Computing, 1980 Vol. 18, Pages. 27-32), Koneshi in U.S. Pat.No. 3,998,550, and Hamaguri in U.S. Pat. No. 4,266,554, which utilized atechnique of analyzing the resultant opto-electronic signal by dividingit into its AC and DC components. The AC and DC components aremanipulated with logarithmic amplifiers in such a way as to eliminatethe above-mentioned transdermal optical effects (the variable amount ofradiation loss due to scattering in the tissue and the unknown andvariable amounts of optical path length increase).

Until now, the AC-DC cancellation techniques have not been successfullyadapted for the measurement of hematocrit or hematocrit-independentblood oxygen saturation.

2. Noninvasive Differential-ratiometric Spectrophotometry

It is assumed that incident radiation passing onto or into a livingtissue will pass through a combination of blood, tissue, andinterstitial fluid compartments. The light attenuated by such a livingtissue can be expressed by the modified Beer-Lambert equation:

ti I=I ₀ e ^(−(ε) ^(_(b)) ^((X) ^(_(a)) ^(+X) ^(_(v)) ^()+ε) ^(_(t))^(X) ^(_(t)) ^(ε) ^(_(i)) ^(X) ^(_(i)) ^()d+G)  (2)

Equation (2) may also be written

ln (I/I ₀)=−(ε_(b)(X _(a) +X _(v))+ε_(t) X _(t)+ε_(i) X _(i))d+G  (2a)

Where ε_(b), ε_(t), and ε_(i) represent the extinction coefficient inthe blood, tissue, and interstitial fluid compartments, respectively;X_(a) and X_(v) represent the arterial and venous blood, concentration(X_(b)=X_(a)+X_(v)), X_(t) represents the concentration of the tissueabsorbers, and X_(i) represents the relative concentration of water anddissolved components in the interstitial fluid compartment; d representsthe intrasensor spacing; and G is a constant of the geometricconfiguration.

As the blood layer pulsates, the concentration terms change. The term dcan be fixed by the geometric configuration of the device. Taking thepartial derivatives of equation (2) with respect to time and dividing byequation (2) gives: $\begin{matrix}{{- \frac{{\partial I}/{\partial t}}{I}} = {( {{\varepsilon_{b}( {{{\partial X_{a}}/{\partial t}} + {{\partial X_{v}}/{\partial t}}} )} + {\varepsilon_{t}{{\partial X_{t}}/{\partial_{t}{+ \varepsilon_{i}}}}{{\partial X_{i}}/{\partial t}}}} ){{{+ {\partial G}}}/{\partial t}}}} & (3)\end{matrix}$

which can be simplified at each compartment and wavelength by lettingX′=∂X/∂t, and G′=∂G/∂t, and$V_{\lambda}^{\prime} = {- ( \frac{{\partial I}/{\partial t}}{I} )_{\lambda}}$

to give

V′ _(λ)=(ε_(b)(X′ _(a) +X′ _(v))+ε_(t) X′ _(t)+ε_(i) X′ _(i))d+G′  (4)

Assuming that X_(t) and G do not vary significantly over the pulse timeinterval, then G′=0 and X′_(t)=0, and equation (4) can be simplified to

V′ _(λ)=(ε_(b)(X′ _(a) +X′ _(v))+ε_(i) X′ _(i))d  (5)

Examining the transport between X_(a) and X_(v), we can form aproportionality constant K_(v) such that X′_(v)=K_(v)X′_(a),representing the reactionary nature of the venous component, and furtherreduce the above equation to

V′ _(λ)=(ε_(b)(1−K _(v))X′ _(a)+ε_(i) +X′ _(i))d  (6)

Since X′_(a) and X′_(i) are not wavelength (λ) dependent, V′_(λ) valuesat different wavelengths can be differentially subtracted to produce ahematocrit independent term which contains only ε_(i)X′_(i) information.Although the term V′₈₀₅/V′₁₃₁₀ provides useful information regardingrelative changes in hematocrit, it should be recognized that the simpleV′₈₀₅/V′₁₃₁₀ ratio is not sufficiently accurate for hematocrit valuedetermination unless the ε_(i)X′_(i) term is known or eliminated. Forexample, the ε_(i)X′_(i805) term can be neglected since ε_(i805) isextremely small, whereas the ε_(i)X′_(i1310) term is about 25%-50% ofthe ε_(b1310) value of blood itself and cannot, therefore, be neglectedwithout affecting accuracy.

FIGS. 11 and 16 suggest that a linear combination of V′_(λ) at λ=805 nmand λ=970 nm will have a near constant value for a range of Hct values.Since the extinction coefficients ε_(i805) and ε_(i970) are well known,or can be empirically determined, a precise proportionality constantR₁.1 can be found to produce

ε_(i970) X _(i) ′=V ₉₇₀ ′−R ₁ V ₈₀₅′  (7)

This correction term can now be applied with a second proportionalityconstant R₂ (where R₂ is approximately equal to ε_(i1310)/ε_(i970)) tothe V′₁₃₁₀ term to exactly remove its ε_(i1310)X′_(i) sensitivity,hence:

ε_(b1310)(1−K _(v))X _(a) ′=V ₁₃₁₀ ′−R ₂(V ₉₇₀ ′−R _(a) V ₈₀₅′)  (8)

This corrected term can now be used ratiometrically with V₈₀₅′ to removethe (1−K_(v))X′_(a) and leave the pure extinction coefficient ratiorepresented by Equation (9) below and shown graphically in FIG. 3.$\begin{matrix}{\frac{\varepsilon_{b805}}{\varepsilon_{b1310}} = \frac{V_{805}^{\prime}}{V_{1310}^{\prime} - {R_{2}( {V_{970}^{\prime} - {R_{1}V_{805}^{\prime}}} )}}} & (9)\end{matrix}$

It should be noticed that the following assumptions and requirements areessential in hematocrit determinations (but in the case of pulseoximetry these requirements may not be of the same degree ofsignificance).

A. Even though wavelengths λ=805 nm and λ=1310 nm are near isobestic,the actual function of ε versus Hematocrit at each given wavelength musthold hematocrit information that is different in curvature, or offset,or linearity, or sign from the other. See FIG. 16. If the functionsε_(λ) versus hematocrit are not sufficiently different, then the ratioε_(bλ1)/ε_(bλ2) will not hold hematocrit information. See FIGS. 12A and12B and FIGS. 13A and 13B. Even though the foregoing discussion refersto the isobestic wavelengths of λ=805 nm and λ=1310 nm, it will beappreciated that other isobestic wavelengths, such as λ=570 nm, λ=589nm, and λ=1550 nm, may also be utilized.

B. Further, the wavelengths should be selected close enough to oneanother such that the optical path lengths, d, are approximately thesame. Longer wavelengths are preferred since they exhibit lesssensitivity to scattering, s: $\begin{matrix}{s \propto \frac{1}{\lambda^{2}}} & (10)\end{matrix}$

C. The geometric or spatial relationship of the emitters and sensors isimportant. For instance, if vertically aligned emitters are used in anearlobe-measuring device, then the top-most emitter may illuminate adifferent amount of blood filled tissue than the lower emitter. If onlyone sensor is used, then there will be a disparity between X′_(b) ateach wavelength. See FIG. 14, wherein X_(b1)>X_(b2)>X_(b3). Furthermore,the sensor-emitter spatial separation distance is very important becausethe pressure applied to the tissue between the sensor and emittersaffects the arteriolar and capillary vessel compliance. This changes theX′ as the pressure (or distance) changes. This change in X′ thenmodulates the V′_(λ) function. Therefore, the sensor-emitter separationdistance must be such that the pressure applied to the earlobe,fingertip, or other body member, does not affect the V′_(λ) function.This sensor separation distance is empirically determined and shouldgenerate less than 40 mm Hg applied transmural pressure.

A horizontal alignment (FIG. 14) of the emitters with respect to thesingle sensor can be arranged so that the emitters and sensorsilluminate and detect identical regions of ∂X_(λ1) and ∂X_(λ2). It isimportant to note that the term d, the sensor-emitter separation, willbe different between λ₁ and λ₂ by the cosine of the angle between thesensor and emitter. Therefore, if any misalignment from normal occurs,the term d will not cancel to obtain equation (9).

The preferred arrangement is wherein all the emitters (660, 805, 950,and 1310 nm) are located on the same substrate. This is preferredbecause the emitters will then illuminate essentially the same X_(b)region.

D. In the case of reflectance spectrophotometry, an aperture for thesensor and each emitter is required. See FIG. 1B. Also, a sensor-emitterseparation is required so that the reflectance of the first layer oftissue, R_(t), (a non-blood layer of epithelium) does not furtherexaggerate a multiple scattering effect, i.e. the total reflectance, R,measured would contain spurious information of the epithelial layers'reflectance as well, where: $\begin{matrix}{R = {R_{t} + \frac{T_{t}^{2} \cdot R_{b}}{( {1 - {R_{b} \cdot R_{t}}} )}}} & (11)\end{matrix}$

where R is the total reflectance, R_(t) is the reflectance due to thefirst tissue-epithelial layer, R_(b) is the reflectance due to the bloodlayer, and T_(t) is the transmission through the first tissue layer.

The reflectance equations describing R_(t) or R_(b) must now sum all ofthe backscattered light that the sensor detects, i.e.,:

R _(b)=∫∫∫(source function)·(scattering function)  (12)

While equation (9) describes the theory of the noninvasive hematocritdevice, the four assumptions (A-D) are important to the repeatabilityand accurate functioning of the hematocrit device.

Assuming items A through D are dealt with appropriately, then (9)becomes: $\begin{matrix}{\frac{\varepsilon_{b\quad {\lambda 1}}}{\varepsilon_{b\quad {\lambda 2}}} = \frac{( {s_{1} + k_{1}} )}{( {s_{2} + k_{2}} )}} & (13)\end{matrix}$

where s is a scattering constant and k is an absorption constant, andwhere in whole blood:

s=σ _(s) Hct(1−Hct)  (14)

 k=σ _(a) Hct(at isobestic wavelengths)  (15)

where σ_(s) is the scattering cross section and σ_(a) is the absorptioncross section.

From the foregoing, e, the extinction coefficient, is not a simplefunction of the absorption coefficient, k, normally determined in puresolutions. Rather, it contains a diffusion or scattering term, s, whichmust be accounted for in a non-pure solution media such as whole bloodand tissue.

Finally, substituting (14) and (15) into (13): $\begin{matrix}{\frac{\varepsilon_{\lambda 1}}{\varepsilon_{\lambda 2}} = \frac{{\sigma_{s1}( {1 - {Hct}} )} + \sigma_{a1}}{{\sigma_{s2}( {1 - {Hct}} )} + \sigma_{a2}}} & (16)\end{matrix}$

Therefore, the ratio ε_(λ1)/ε_(λ2) is a function of hematocrit. FromFIG. 3, a look up table or polynomial curve fit equation may be obtainedand utilized in the final displayed hematocrit results. Knowing theactual hematocrit value, it is straightforward to see (FIG. 2) that awavelength at 660 nanometers can be selected to obtain an ε ratiowherein the hematocrit-independent oxygen saturation value is derived.For example, equation (16) would become: $\begin{matrix}{\frac{ɛ_{b660}}{\varepsilon_{b805}} = \frac{{\sigma_{s660}( {1 - {Hct}} )} + \sigma_{a660} - {S_{a}{O_{2}( {\sigma_{ao660} - \sigma_{ar660}} )}}}{{\sigma_{s805}( {1 - {Hct}} )} + \sigma_{a805} - {S_{a}{O_{2}( {\sigma_{ao805} - \sigma_{as805}} )}}}} & (17)\end{matrix}$

Equation (17) shows both the hematocrit and oxygen saturation dependenceon each other.

FIG. 10 graphically demonstrates the need for a hematocrit-independentblood saturation device. As either the hematocrit value or percentoxygen saturation decreases, the percent saturation error becomesunacceptable for clinical usage. For example, it is not uncommon to seepatients with a low hematocrit (about 20%) who have respiratoryembarrassment (low oxygen saturation) as well. Hence, the cliniciansimply requires more accurate oxygen saturation values.

Knowing the hematocrit and oxygen saturation values, the computation ofthe Oxygen Content is trivial and may be displayed directly (a valueheretofore unavailable to the clinician as a continuous, real-time,noninvasive result):

[Oxygen Content]=Hct•S_(a)O₂ •K  (18)

where K is an empirically determined constant.

Referring to the equations (16) and (9) a decision must be made by thecomputer as to the suitability of utilizing the Taylor expansionapproximation to the logarithm. This algorithm is maintained in thesoftware as a qualifying decision for the averaging and readoutalgorithms. The Taylor approximation is only valid for small ∂I/∂tvalues.

3. Nonpulsatile Applications

a. Valsalva's Maneuver to Simulate Pulsatile Case

It is interesting to see the similarities between this AC pulsatilederivation and an analogous DC technique. By taking the logarithm of twointensity ratios, values of ε_(b) and ε_(i) can be obtained from themodified Beer-Lambert equation (equation (2a)). These same extinctioncoefficients can be manipulated by the identical proportionalityconstants R₁ and R₂ found previously to exactly eliminate ε_(i1310)X_(i)and yield $\begin{matrix}{\frac{\varepsilon_{b805}}{\varepsilon_{b1310}} = \frac{U_{805}}{U_{1310} - {R_{2}( {U_{970} - {R_{1}U_{805}}} )}}} & (19)\end{matrix}$

Where the term$U_{\lambda} = {\ln ( \frac{I_{2}}{I_{1}} )}_{\lambda}$

represents the logarithm of intensity ratios at X_(b) values of X₁ andX₂.

It should also be noted that the two derivations (AC and DC) fold intoone another through the power series expansion of the ln(1+Z) function:$\begin{matrix}{{{\ln ( {1 + Z} )} = {Z - \frac{Z^{2}}{2} + \frac{Z^{3}}{3} - \ldots}}\quad} & (20)\end{matrix}$

When the value ΔI=I₂−I₁, it can be seen that $\begin{matrix}\begin{matrix}{{\ln ( \frac{I_{2}}{I_{1}} )} = {{\ln ( \frac{{\Delta \quad I} + I_{1}}{I_{1}} )} = {\ln ( {1 + \frac{\Delta \quad I}{I_{1}}} )}}} \\{= {\frac{\Delta \quad I}{I} + {{High}\quad {Order}\quad {Terms}}}}\end{matrix} & (21)\end{matrix}$

which means that for small changes in X_(b), the AC (partial derivative)and DC (logarithmic) derivations are similar and can each be-preciselycompensated through this differential-ratiometric technique to providean noninvasive ε_(b805)/ε_(b1310) ratio which is independent of both theconstant and time-varying tissue and interstitial fluid terms.

One currently preferred method of obtaining the two intensity ratios isto have the patient perform Valsalva's maneuver. Valsalva's maneuver isan attempt to forcibly exhale with the glottis, nose, and mouth closed.This maneuver increases intrathoracic pressure, slows the pulse,decreases return of blood to the heart, and increases venous pressureobtaining intensity measurements before and during Valsalva's maneuverprovide sufficiently different intensity ratios to utilize equation(19). Even a deep breath can be enough to obtain sufficiently differentintensity ratios.

b. Stepper Motor Technique

Another technique to simulate pulsatile blood flow and to eliminate theskin's optical scattering effects, while at the same time preserving theblood-borne hematocrit and oxygen saturation information, is describedbelow. By utilizing a stepper motor 9 in the earlobe clip assembly 10 onan earlobe 11 of a patient, such as that illustrated in FIGS. 5, 5A, 14,and 15, one can produce a variation of X_(b) sufficient to utilizeequation 19. The stepper motor 9 could even produce a bloodless(X_(b)=0) state, if required. However, equation 19 shows that only adifference between X_(b1) and X_(b2) is needed.

The major advantage of this technique is that under clinical conditionsof poor blood flow, poor blood pressure, or peripheral vascular disease,where pulse wave forms are of poor quality for the (∂I/∂t)/I technique,this DC-stepper motor technique could be utilized.

C. Oxygen Saturation Determination

The above techniques describe conditions and equations wherein isobesticwavelengths are chosen such that the hematocrit value obtained has nointerference from oxygen saturation, hence an independently determinedhematocrit value.

One, however, may choose λ₂ (the reference wavelength) in equation (13)at 1550 nm as well. In the radiation region 900 to 2000 nm the bloodabsorption coefficients depend on hematocrit and water, whereas at 805nm the blood absorption coefficient only depends on hematocrit.Therefore, utilizing in combination, wavelengths of 660, 805, and 1550will also give a technique to determine hematocrit (ε₈₀₅/ε₁₅₅₀) andoxygen saturation (ε₆₆₀/ε₈₀₅)

These 3 wavelengths are particularly important since 660, 805, and 1550nm (or 1310 nm) are readily available LEDs, such as, respectively,MLED76-Motorola, HLP30RGB-Hitachi, and ETX1550-EPITAXX (or NDL5300-NEC),with the benefits of low cost and low optical power (reducing anyquestion of possible eye damage).

The manufacturing of a multi-chip LED emitter becomes reasonable,cost-wise, and provides increased accuracy since the LED sources havepractically no separation distances and appear as a single point source.

This invention may be applied to the determination of other components(included, but not limited to, glucose, or cholesterol) in any range ofthe electromagnetic spectrum in which spectrophotometric techniques canbe utilized.

4. Currently Preferred Apparatus

An earlobe clip assembly 10 as in FIGS. 5, 5A, 14, and 15 (with orwithout the stepper motor 9 shown in FIG. 6A) and a finger clip assembly6 used on a finger 7 of a patient as shown in FIGS. 1, 1A, and 1B, aretwo currently preferred embodiments for practicing the presentinvention. The photodiodes 3 and emitters 1 and 2 in each are placed inaccordance with appropriate alignment.

Consider first the sensor technology in the transmissive mode ofoperation. An earlobe or fingertip housing can be provided with discreetemitters and two photodiode chips (of different sensitivity ranges,600-1000 nm and 1000-1700 nm ranges) placed on one substrate, such as aTO-5 can (Hamamatsu K1713-03). The emitters likewise can be two or moreemitter chips (i.e., λ=805, 1310, 660, and 950 nm) placed on a commonsubstrate and illuminated through a TO-39 can.

Finally, a single substrate multi-wavelength emitter and amulti-wavelength detector, assembled in one small physical housing foreach, make alignment and detection sensitivity more repeatable, andhence-more accurate.

The preferred emitter chips would have wavelengths, for hematocrit-onlymeasurements, at 805 nm, 950 nm, and 1310 nm (or 805 nm, 950 nm, and1550 nm). Although in theory, an emitter having a wavelength of 970nanometers, rather than 950 nm, would provide more accurate information,970 nm emitters are not presently available commercially. Thesewavelengths are currently preferred because of the different curvatureand baseline offset of the ε versus Hematocrit at those wavelengths. SeeFIG. 16. Hence, the hematocrit information will exist in the ratioε_(λ1)/ε_(λ12). See FIG. 3.

Furthermore, the choice of 805 nm and 1310 nm (or 1550 nm) rather than570 nm and 805 nm is because there is no water absorption in the 570 nm(or 589 nm) and 805 nm isobestic wavelengths. However, there istremendous water absorption at 1310 nm and 1550 nm. Hence, the ratio of570 nm to 805 nm, as a reference, would not yield hematocrit informationbecause there would be no offset due to water in the plasma. See FIGS.12A and 12B and FIGS. 13A and 13B.

If hematocrit-independent oxygen saturation is desired then the emitterchip wavelengths would be 660 nm, 805 nm, 950 nm, and 1310 nm (or 1550nm) (the 660 nm is MLED76, Motorola or TOLD 9200, Toshiba). Likewise,the photodetector single substrate could house at least two chips, suchas a Hamamatsu K1713-03.

It will be appreciated that those skilled in the art would be able toadd other chips to the single substrate at wavelengths sensitive toother metabolites (glucose, cholesterol, etc.). The above mentionedemitter and detector connections can be seen in the analog schematicdiagram illustrated in FIGS. 6 and 8B-8D.

The sensor technology in the reflectance mode must conform to twoembodiment parameters. See FIG. 1B. The diameter and thickness of theaperture 8 of finger clip assembly 6 in which finger 7 is received incombination with the sensor-emitter separation distances are importantto provide a detection region within the subdermis 12 at points a and bof FIG. 1B, where the radiation impinges on blood-tissue without themultiple scattering effects of the epithelial layer, R_(t). Thedetermination of optimum sensor 3 separation and aperture 8 sizes isdone empirically from numerous finger 7 with varying callous andfingernails 13. Minimum sensor separation and aperture diameters can beestablished wherein R_(t), of equation (14) is eliminated.

FIGS. 6, 7A-7C, 8A-8D, and 9A-9B detail the electronics of one circuitsuitable for use within the scope of the present invention. The memoryand computation means (FIGS. 7A-7C) are connected via a “bus” structurebetween PROMS (U110,U111), microprocessor MC68HC000 (U106), static RAMS(U112,U113), and isolation buffers to the low-level analog circuitry(FIG. 6). A crystal controlled oscillator circuit (U101A,B) is dividedby 2 to provides a symmetric master clock to the microprocessor; thisclock is further subdivided and used to provide clocking for theanalog-to-digital converter0 (U208) and timer (U109). Strobe lines aregenerated through a decoder arrangement to drive each of the subsystemsof the device and also control the isolation bus buffers (U201,U202).

Timer outputs are fed back into the microprocessor and encoded (U104) toproduce interrupts at specific intervals for system functions. One timeris shared by subsystems which control the liquid crystal display means,the keyboard entry means, the audible indicator, and the cyclingbackground system self-test. Another timer is dedicated exclusively toprovide a high priority interrupt to the microprocessor; this interruptdrives software which controls the basic sensor sampling mechanism. Anexpansion connector (J101) is included to allow extended testing of thedevice or connection to external data-logging equipment such as aprinter or computer interface.

The local bus isolates the sensitive analog circuitry from the maindigital circuitry. This prevents spurious crosstalk from digital signalsinto the analog circuitry and thereby reduces superimposed noise on themeasured signals. It is on this local bus that the Digital-to-AnalogConverters (DAC) and Analog-to-Digital Convertors (ADC) transmit andreceive digital information while processing the low-level. analogsignals.

The Low Level Sensor electronic section, FIG. 6, combines subsystems toboth measure and modulate the current produced from each optical sensor.Since a pulsatile component of the optical energy transmitted through orreflected off of tissue comprises only a small part of the overalloptical energy incident on the sensor, means are provided to “null out”in a carefully controlled and accurately known way the non-pulsatilecomponent of the light-produced current in the sensing detector. Theremaining signal can then be dc-amplified and filtered in astraightforward manner and presented to the ADC (U208) for conversioninto a digital value representative of the relative AC pulsatilecomponent. Furthermore, because the relationship between the nullingcurrent and the average value of this AC component is known, the DCcomponent can easily be calculated as a function of the sensing means'sensitivities and the electronic stages' gains. The functionsdetermining these AC and DC values can (if necessary) be trimmed insoftware by calibration constants which sire stored in EEPROM (U307) andretrieved each time the unit is powered on.

The current which modulates the optical sources (LEDs or laser diodes)is also controlled (U203) and precisely adjusted (U306) to optimizesignal reception and detection. Through software control, the modulationcurrent can be adjusted on a pulse-by-pulse basis to minimizenoise-induced inaccuracies. Furthermore, by sampling the sensors withthe modulation sources disabled appropriately, background noise (such as60 Hz) can be rejected digitally as common-mode noise. Thus, bycontrolling the optical source energy and modulating the nulling currentin the photosensor circuitry, it is possible to effectively cancel theeffects of ambient radiation levels and accurately measure both thestatic (DC) and time-varying (AC) components of transmitted or reflectedlight.

Interrupt-driven software algorithms acquire the sensor data, provide areal-time pulse wave contour, and determine pulse boundaries. Completedbuffers (i.e. one entire pulse per buffer) of sensor data are thenpassed to the foreground software processes for computation. Thisinvolves the determination of the background-compensated AC pulsatileand DC static values of intensities for each wavelength. Throughaveraging and selective elimination of abnormal values, results are thencalculated using equation (9) and displayed on the LCD. The modulatingand nulling currents are (if necessary) also adjusted to utilize theelectronic hardware efficiently and optimally.

5. Summary

Although the foregoing discussion has related to noninvasive analysis ofblood hematocrit information, it will be appreciated that theabove-mentioned emitters, sensors, and circuitry may be adapted forinvasive in vitro analysis of blood hematocrit values. The principleswithin the scope of the present invention which compensate for spatial,geometric, and tissue variations may be used to compensate for similarvariations in an in vitro blood container. Such a device would allowhematocrit values to be determined rapidly and accurately.

Those skilled in the art will also appreciate that the methods withinthe scope of the present invention for determining blood hematocritvalues may be adapted for determining non-hematocrit biologicconstituent values such as glucose, cholesterol, etc. To determinebiologic constituent information, the effects of competing blood,tissue, and interstitial fluid constituents must be eliminated. It isbelieved that these effects may be eliminated by appropriatemodification of the differential ratiometric techniques described above.

It is important to recognize that the present invention is not directedto determining the tissue hematocrit value. The tissue hematocrit value,in contrast with the blood hematocrit value, reflects the amount of redblood cells in a given volume of tissue (blood, interstitial fluids,fat, hair follicles, etc.). The present invention is capable ofdetermining actual intravascular blood hematocrit and hemoglobin values.

From the foregoing, it will be appreciated that the present inventionprovides a system and method for noninvasively and quantitativelydetermining a subject's hematocrit or other blood constituent value. Thepresent invention determines the hematocrit noninvasively by utilizingelectromagnetic radiation as the transcutaneous information carrier.Importantly, the present invention may be used on various body parts toprovide accurate quantitative hematocrit values.

It will also be appreciated that the present invention also provides asystem and method which can provide immediate and continuous hematocritinformation for a subject. The present invention further provides asystem and method for noninvasively determining a subjects's bloodoxygen saturation (S_(a)O₂) independent of the subject's hematocrit. Inaddition, the present invention provides a system and method fornoninvasively determining a subject's hematocrit and/or blood oxygensaturation even under conditions of low blood perfusion.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed and desired to be secured by United States LettersPatent is:
 1. A method for determining hematocrit of blood of a patient,the blood flowing in a pulsatile fashion in a body part of the patientor in an extracorporeal passageway in communication with the circulatorysystem of the patient so as to be subjectable to transcutaneousexamination in the body part or to noninvasive examination in theextracorporeal passageway, the body part and the extracorporealpassageway defining a blood conduit and the method comprising the stepsof: (a) selecting a first radiation wavelength that is isobestic for Hband HbO₂ and not extinguished by non-hemoglobin components of the blood;(b) selecting a second radiation wavelength that is isobestic for Hb andHbO₂ and extinguished by non-hemoglobin components of the blood; (c)directing the first radiation wavelength into the blood conduit; (d)directing the second radiation wavelength into the blood conduit; (e)detecting the amount of steady state component of the first wavelengthextinguished after passing through the blood conduit; (f) detecting theamount of steady state component of the second wavelength extinguishedafter passing through the blood conduit; (g) detecting the amount ofpulsatile component of the first wavelength; (h) detecting the amount ofpulsatile component of the second wavelength; (i) determining a ratio ofthe pulsatile component of the first wavelength to the steady statecomponent of the first wavelength; (j) determining a ratio of thepulsatile component of the second wavelength to the steady statecomponent of the second wavelength; (k) obtaining a mean value for theratio of the pulsatile component of the first wavelength to the steadystate component of the first wavelength over a period of time; (l)obtaining a mean value for the ratio of the pulsatile component of thesecond wavelength to the steady state component of the second wavelengthover a period of time; and (m) determining the hematocrit by the ratioof the mean values obtained for the first and second wavelengths.
 2. Themethod for determining the hematocrit of the blood of a patient of claim1, further comprising the steps of: (n) displaying the hematocrit. 3.The method for determining the hematocrit of the blood of a patient ofclaim 1, further comprising the steps of: (n) selecting a thirdradiation wavelength; (o) directing the third radiation wavelength intothe blood conduit; (p) determining a mean value for a ratio of pulsatilecomponent of the third wavelength to steady state component of the thirdwavelength over a period of time; and (q) calculating a correctedhematocrit value using a linear combination of the first, second andthird wavelengths and their ratios.
 4. The method for determining thehematocrit of the blood of a patient of claim 3, further comprising thesteps of: (r) display the corrected hematocrit value.
 5. A system fordetermining hematocrit of blood of a patient, the blood flowing in apulsatile fashion in a body part of the patient or in an extracorporealpassageway in communication with the circulatory system of the patientso as to be subjectable to transcutaneous examination in the body partor to noninvasive examination in the extracorporeal passageway, the bodypart and the extracorporeal passageway defining a blood conduit, thesystem comprising: (a) blood conduit receiving means for receiving ablood conduit containing the flowing blood of the patient; (b) a firstemitter positioned on said conduit receiving means for emitting a firstradiation wavelength that is isobestic for Hb and HbO₂ and notextinguished by non-hemoglobin components of the blood; (c) a secondemitter positioned on said conduit receiving means for emitting a secondradiation wavelength that is isobestic for Hb and HbO₂ and extinguishedby non-hemoglobin components of the blood; (d) means for directing thefirst radiation wavelength into the blood conduit; (e) means fordirecting the second radiation wavelength into the blood conduit; (f)means for detecting the amount of steady state component of the firstwavelength extinguish after passing through the blood conduit; (g) meansfor detecting the amount of steady state component of the secondwavelength extinguished after passing through the blood conduit; (h)means for detecting the amount of pulsatile component of the firstwavelength; (i) means for detecting the amount of pulsatile component ofthe second wavelength; (j) means for determining a ratio of thepulsatile component of the first wavelength to the steady statecomponent of the first wavelength; (k) means for determining a ratio ofthe pulsatile component of the second wavelength to the steady statecomponent of the second wavelength; (l) means for obtaining a mean valuefor the ratio of the pulsatile component of the first wavelength to thesteady state component of the first wavelength over a period of time;(m) means for obtaining a mean value for the ratio of the pulsatilecomponent of the second wavelength to the steady state component of thesecond wavelength over a period of time; and (n) means for determiningthe hematocrit by the ratio of the mean values obtained for the firstand second wavelengths.
 6. The system for determining the hematocrit ofthe blood of a patient of claim 5, further comprising: (o) means fordisplaying the hematocrit.
 7. The system for determining the hematocritof the blood of a patient of claim 5, further comprising: (o) a thirdemitter positioned on said conduit receiving means for emitting a thirdradiation wavelength; (p) means for directing the third radiationwavelength into the blood conduit; (q) means for determining a meanvalue for a ratio of pulsatile component of the third wavelength tosteady state component of the third wavelength over a period of time;and (r) means for calculating a corrected hematocrit value using alinear combination of the first, second and third wavelengths and theirratios.
 8. The system for determining the hematocrit of the blood of apatient of claim 7, further comprising: (s) means for display thecorrected hematocrit value.